1. Field of the Invention
The invention provides materials and methods relating to identification and optimization of selective inhibitors of glycogen synthase kinase 3 (GSK3), and also relates to methods of treating a condition mediated by GSK3 activity. Such conditions include Alzheimer's disease, type 2 diabetes, and inflammation.
2. Description of the Related Art
Glycogen synthase kinase 3 (GSK3) is a proline-directed serine/threonine kinase originally identified as an activity that phosphorylates glycogen synthase as described in Woodgett, Trends Biochem Sci. 16:177–181 (1991). The role in glucose metabolism has been elaborated recently in Summers et al., J. Biol. Chem. 274:17934–17940 (1999). GSK3 consists of two isoforms, α and β, and is constitutively active in resting cells, inhibiting glycogen synthase by direct phosphorylation. Upon insulin activation, GSK3 is inactivated, thereby allowing the activation of glycogen synthase and possibly other insulin-dependent events. GSK3 is inactivated by other growth factors or hormones that, like insulin, signal through receptor tyrosine kinases. Examples of such signaling molecules include IGF-1 and EGF as described in Saito et al., Biochem. J. 303:27–31 (1994), Welsh et al., Biochem. J. 294:625–629 (1993), and Cross et al., Biochem. J. 303:21–26 (1994). GSK3 has been shown to phosphorylate β-catenin as described in Peifer et al., Develop. Biol. 166:543–56 (1994). Other activities of GSK3 in a biological context include GSK3's ability to phosphorylate tau protein in vitro as described in Mandelkow and Mandelkow, Trends in Biochem. Sci. 18:480–83 (1993), Mulot et al., Febs Lett 349: 359–64 (1994), and Lovestone et al., Curr. Biol. 4:1077–86 (1995), and in tissue culture cells as described in Latimer et al., Febs Lett 365:42–6 (1995). Selective inhibition of GSK3/may be useful to treat or inhibit disorders mediated by GSK3 activity.
There is a need in the art for compositions and molecules that bind to or interact with GSK3, thereby mediating GSK3 activity. The invention meets this need by providing crystallizable GSK3 polypeptides useful for design and optimization of GSK3 inhibitors.